BACKGROUND. Residual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known. METHODS. We studied sixty-three adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007; n =15), low (0.017–0.200; n =16), intermediate (>0.200–0.400; n =15), or high (>0.400 pmol/mL; n =17). We compared the groups’ glycemia from continuous glucose monitoring (CGM), β-cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemia euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp. RESULTS. Low and intermediate MMTT C-peptide groups did not exhibit β-cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P <0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared to the negative group (P ≤0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared to negative (P =0.01). CGM demonstrated lower mean glucose and more time-in-range for the high C-peptide group. CONCLUSION. These results indicate that in adults with type 1 diabetes, β-cell responsiveness to hyperglycemia and α-cell responsiveness to hypoglycemia are only observed at high levels of residual C-peptide that likely contribute to glycemic control.
Michael R. Rickels, Carmella Evans-Molina, Henry T. Bahnson, Alyssa Ylescupidez, Kristen J. Nadeau, Wei Hao, Mark A. Clements, Jennifer L. Sherr, Richard E. Pratley, Tamara S. Hannon, Viral N. Shah, Kellee M. Miller, Carla J. Greenbaum